PROJECT SUMMARY Although major depressive disorder (MDD) is among the most prevalent psychiatric disorders and is one of the most burdensome diseases in the world, understanding of its etiology is limited. Research has shown that the development of depression is multiply determined by biological and psychosocial factors. The emerging and exciting field of behavioral epigenetics lies at the intersection of biological and environmental explanations for disorder in positing that stressful life events ?get under the skin? through epigenetic modifications like DNA methylation to confer risk for depression. Using data from over 1,000 adolescents in a longitudinal birth cohort study in the UK (the Avon Longitudinal Study of Parents and Children; ALSPAC) we aim to conduct (1) epigenome-wide analyses (measuring DNA methylation at birth and in adolescence) to identify genes that are differentially methylated in adolescents who are on a high vs. low depression trajectory, (2) epigenome-wide analyses to identify associations between stressful life events (in utero and in early adolescence) and DNA methylation at the corresponding development period, and (3) mediational analyses to test the indirect effect of stressful life events in utero and in adolescence on depression symptom trajectories in adolescence via DNA methylation. The proposed research would be the first to test the full pathway by which stressful life events increase risk for depression via epigenetic modifications. The proposed research is highly innovative in applying a developmental lens to the question of how stressful exposures become biologically embedded. This developmental approach will be used to refine the depression phenotype (by identifying trajectory groups who are homogeneous in symptom onset, course, and severity) and to ask questions that are novel to behavioral epigenetics, including questions about sensitive periods for the effect of stressful life events and epigenetic alterations and questions about the stability of epigenetic modifications over time. Because research has shown that epigenetic markings are reversible, the proposed research has the potential to inform efforts to prevent the onset and recurrence of depression. This project and the accompanying training plan will prepare the applicant for a research career investigating epigenetic modifications as potential mechanisms by which exposure to various forms of stress is translated into risk for psychopathology.